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Updated: Jul 1, 2025
Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells
Published on: July 18, 2019
Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis
Christian Sommerauer1, Carlos J Gallardo-Dodd1, Christina Savva2
1Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Science for Life Laboratory, Solna, Sweden.
Abstract:
Sex-based differences in obesity-related hepatic malignancies suggest the protective roles of estrogen. Using a preclinical model, we dissected estrogen receptor (ER) isoform-driven molecular responses in high-fat diet (HFD)-induced liver diseases of male and female mice treated with or without an estrogen agonist by integrating liver multi-omics data. We found that selective ER activation recovers HFD-induced molecular and physiological liver phenotypes. HFD and systemic ER activation altered core liver pathways, beyond lipid metabolism, that are consistent between mice and primates. By including patient cohort data, we uncovered that ER-regulated enhancers govern central regulatory and metabolic genes with clinical significance in metabolic dysfunction-associated steatotic liver disease (MASLD) patients, including the transcription factor TEAD1. TEAD1 expression increased in MASLD patients, and its downregulation by short interfering RNA reduced intracellular lipid content. Subsequent TEAD small molecule inhibition improved steatosis in primary human hepatocyte spheroids by suppressing lipogenic pathways. Thus, TEAD1 emerged as a new therapeutic candidate whose inhibition ameliorates hepatic steatosis.
Insights
Estrogen receptor activation reverses high-fat diet liver damage in mice. This pathway involves TEAD1, a key factor in metabolic dysfunction-associated steatotic liver disease, offering a new therapeutic target.
Area of Science:
- Endocrinology
- Hepatology
- Molecular Biology
Background:
- Obesity-related liver diseases show sex-based differences, implicating estrogen's protective role.
- Estrogen receptor (ER) signaling is crucial in regulating liver physiology and metabolism.
Purpose of the Study:
- To investigate ER isoform-specific responses in high-fat diet (HFD)-induced liver disease.
- To identify molecular mechanisms linking ER activation to liver health and metabolic dysfunction-associated steatotic liver disease (MASLD).
Main Methods:
- Utilized a preclinical mouse model with HFD and selective ER activation.
- Integrated multi-omics data (genomics, transcriptomics, metabolomics) from mouse livers and human patient cohorts.
- Employed short interfering RNA (siRNA) and small molecule inhibitors in cellular models.
Main Results:
- Selective ER activation restored HFD-induced liver phenotypes in mice.
- ER activation modulated core liver pathways beyond lipid metabolism, conserved across species.
- ER-regulated enhancers control key metabolic genes in MASLD patients, including transcription factor TEAD1.
- TEAD1 downregulation and small molecule inhibition reduced hepatic steatosis in vitro.
Conclusions:
- Estrogen receptor signaling plays a vital role in mitigating HFD-induced liver injury.
- TEAD1 is a critical mediator in MASLD pathogenesis and a potential therapeutic target for hepatic steatosis.
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